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Search for cardiac calcium cycling gene mutations in familial ventricular arrhythmias resembling catecholaminergic polymorphic ventricular tachycardia.

Marjamaa A, Laitinen-Forsblom P, Lahtinen AM, Viitasalo M, Toivonen L, Kontula K, Swan H - BMC Med. Genet. (2009)

Bottom Line: A rare variant (N3308S) with open probabilities similar to the wild type channels in vitro, was evident in a patient with resting VPCs.No disease-causing variants were detectable in the FKBP1B, ATP2A2 or SLC8A1 genes.We report two novel CPVT-causing RyR2 mutations and a novel RyR2 variant of uncertain clinical significance in a patient with abundant resting VPCs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cardiology, University of Helsinki, Helsinki, Finland. annukka.marjamaa@helsinki.fi

ABSTRACT

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited cardiac disorder caused by mutations predominantly in the ryanodine receptor (RyR2) gene. We sought to identify mutations in genes affecting cardiac calcium cycling in patients with CPVT and in less typical familial exercise-related ventricular arrhythmias.

Methods and results: We recruited 33 consecutive patients with frequent ventricular premature complexes (VPCs) without structural heart disease and often history of syncope or sudden death in family. Sixteen of the patients featured a phenotype typical of CPVT. In 17 patients, VPCs emerged also at rest. Exercise stress test and echocardiography were performed to each patient and 232 family members. Familial background was evident in 42% of cases (n = 14). We sequenced all the coding exons of the RyR2, FKBP1B, ATP2A2 and SLC8A1 genes from the index patients. Single channel recordings of a mutant RyR2 were performed in planar lipid bilayers. Two novel RyR2 missense mutations (R1051P and S616L) and two RyR2 exon 3 deletions were identified, explaining 25% of the CPVT phenotypes. A rare variant (N3308S) with open probabilities similar to the wild type channels in vitro, was evident in a patient with resting VPCs. No disease-causing variants were detectable in the FKBP1B, ATP2A2 or SLC8A1 genes.

Conclusion: We report two novel CPVT-causing RyR2 mutations and a novel RyR2 variant of uncertain clinical significance in a patient with abundant resting VPCs. Our data also strengthen the previous assumption that exon 3 deletions of RyR2 should screened for in CPVT and related phenotypes.

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Sample ECG recordings from the exercise stress tests in the Group A and B. A 33-year-old male patient from Group A reported exercise-induced syncope since the age of 14. Resting ECG was normal except for a relative bradycardia of 45 bpm (1). After the threshold heart rate of 128 bpm, the exercise stress test revealed polymorphic VPCs typical of CPVT (2) that disappeared in the recovery phase (3). Three of the 16 examined individuals in the family had a similar phenotype and carried the RyR2 exon 3 deletion. The 57-year-old female patient in Group B showed frequent VPCs in baseline ECG (4), in the exercise stress test (5) and in the recovery phase (6). A total of 13 patients of the 77 clinically evaluated subjects in the family featured a similar atypical phenotype. No disease-causing variants were detectable in the screened genes.
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Figure 1: Sample ECG recordings from the exercise stress tests in the Group A and B. A 33-year-old male patient from Group A reported exercise-induced syncope since the age of 14. Resting ECG was normal except for a relative bradycardia of 45 bpm (1). After the threshold heart rate of 128 bpm, the exercise stress test revealed polymorphic VPCs typical of CPVT (2) that disappeared in the recovery phase (3). Three of the 16 examined individuals in the family had a similar phenotype and carried the RyR2 exon 3 deletion. The 57-year-old female patient in Group B showed frequent VPCs in baseline ECG (4), in the exercise stress test (5) and in the recovery phase (6). A total of 13 patients of the 77 clinically evaluated subjects in the family featured a similar atypical phenotype. No disease-causing variants were detectable in the screened genes.

Mentions: VPCs appeared in 16 cases solely upon physical exercise but not in resting conditions thus resembling the arrhythmias of classical catecholaminergic polymorphic ventricular tachycardia (Group A) [1,17,18]. In seventeen of the 33 patients, frequent VPCs were also observed at rest and at the recovery phase of the exercise stress test (Group B) as illustrated by an exemplary ECG recording (Figure 1) and by bar graphs summarizing the number of VPCs per hour in the 24 h Holter recordings (Figure 2). The clinical data from the subjects are summarized in Table 1. In the two groups, the mean age of onset was 26 ± 17 years. In the exercise stress tests, the number of successive VPCs was greater in the CPVT phenotype, but the difference was not statistically significant between the two groups (p = 0.08). The probands in the group B had statistically significantly more VPCs (p < 0.001) and more consecutive ventricular complexes (p < 0.01) than the CPVT patients in the 24 h ECG recordings. A total of six probands (38%) in the group A had relatives featuring similar arrhythmias in the clinical evaluation, whereas in the group B, seven probands (41%) had affected relatives. In group A, there were more syncopal spells and sudden juvenile deaths in the first and second-degree relatives, but the difference to group B was not statistically significant. In both phenotypes, one index patient had suffered from juvenile (≤ 40 years) sudden cardiac death.


Search for cardiac calcium cycling gene mutations in familial ventricular arrhythmias resembling catecholaminergic polymorphic ventricular tachycardia.

Marjamaa A, Laitinen-Forsblom P, Lahtinen AM, Viitasalo M, Toivonen L, Kontula K, Swan H - BMC Med. Genet. (2009)

Sample ECG recordings from the exercise stress tests in the Group A and B. A 33-year-old male patient from Group A reported exercise-induced syncope since the age of 14. Resting ECG was normal except for a relative bradycardia of 45 bpm (1). After the threshold heart rate of 128 bpm, the exercise stress test revealed polymorphic VPCs typical of CPVT (2) that disappeared in the recovery phase (3). Three of the 16 examined individuals in the family had a similar phenotype and carried the RyR2 exon 3 deletion. The 57-year-old female patient in Group B showed frequent VPCs in baseline ECG (4), in the exercise stress test (5) and in the recovery phase (6). A total of 13 patients of the 77 clinically evaluated subjects in the family featured a similar atypical phenotype. No disease-causing variants were detectable in the screened genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2667497&req=5

Figure 1: Sample ECG recordings from the exercise stress tests in the Group A and B. A 33-year-old male patient from Group A reported exercise-induced syncope since the age of 14. Resting ECG was normal except for a relative bradycardia of 45 bpm (1). After the threshold heart rate of 128 bpm, the exercise stress test revealed polymorphic VPCs typical of CPVT (2) that disappeared in the recovery phase (3). Three of the 16 examined individuals in the family had a similar phenotype and carried the RyR2 exon 3 deletion. The 57-year-old female patient in Group B showed frequent VPCs in baseline ECG (4), in the exercise stress test (5) and in the recovery phase (6). A total of 13 patients of the 77 clinically evaluated subjects in the family featured a similar atypical phenotype. No disease-causing variants were detectable in the screened genes.
Mentions: VPCs appeared in 16 cases solely upon physical exercise but not in resting conditions thus resembling the arrhythmias of classical catecholaminergic polymorphic ventricular tachycardia (Group A) [1,17,18]. In seventeen of the 33 patients, frequent VPCs were also observed at rest and at the recovery phase of the exercise stress test (Group B) as illustrated by an exemplary ECG recording (Figure 1) and by bar graphs summarizing the number of VPCs per hour in the 24 h Holter recordings (Figure 2). The clinical data from the subjects are summarized in Table 1. In the two groups, the mean age of onset was 26 ± 17 years. In the exercise stress tests, the number of successive VPCs was greater in the CPVT phenotype, but the difference was not statistically significant between the two groups (p = 0.08). The probands in the group B had statistically significantly more VPCs (p < 0.001) and more consecutive ventricular complexes (p < 0.01) than the CPVT patients in the 24 h ECG recordings. A total of six probands (38%) in the group A had relatives featuring similar arrhythmias in the clinical evaluation, whereas in the group B, seven probands (41%) had affected relatives. In group A, there were more syncopal spells and sudden juvenile deaths in the first and second-degree relatives, but the difference to group B was not statistically significant. In both phenotypes, one index patient had suffered from juvenile (≤ 40 years) sudden cardiac death.

Bottom Line: A rare variant (N3308S) with open probabilities similar to the wild type channels in vitro, was evident in a patient with resting VPCs.No disease-causing variants were detectable in the FKBP1B, ATP2A2 or SLC8A1 genes.We report two novel CPVT-causing RyR2 mutations and a novel RyR2 variant of uncertain clinical significance in a patient with abundant resting VPCs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cardiology, University of Helsinki, Helsinki, Finland. annukka.marjamaa@helsinki.fi

ABSTRACT

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited cardiac disorder caused by mutations predominantly in the ryanodine receptor (RyR2) gene. We sought to identify mutations in genes affecting cardiac calcium cycling in patients with CPVT and in less typical familial exercise-related ventricular arrhythmias.

Methods and results: We recruited 33 consecutive patients with frequent ventricular premature complexes (VPCs) without structural heart disease and often history of syncope or sudden death in family. Sixteen of the patients featured a phenotype typical of CPVT. In 17 patients, VPCs emerged also at rest. Exercise stress test and echocardiography were performed to each patient and 232 family members. Familial background was evident in 42% of cases (n = 14). We sequenced all the coding exons of the RyR2, FKBP1B, ATP2A2 and SLC8A1 genes from the index patients. Single channel recordings of a mutant RyR2 were performed in planar lipid bilayers. Two novel RyR2 missense mutations (R1051P and S616L) and two RyR2 exon 3 deletions were identified, explaining 25% of the CPVT phenotypes. A rare variant (N3308S) with open probabilities similar to the wild type channels in vitro, was evident in a patient with resting VPCs. No disease-causing variants were detectable in the FKBP1B, ATP2A2 or SLC8A1 genes.

Conclusion: We report two novel CPVT-causing RyR2 mutations and a novel RyR2 variant of uncertain clinical significance in a patient with abundant resting VPCs. Our data also strengthen the previous assumption that exon 3 deletions of RyR2 should screened for in CPVT and related phenotypes.

Show MeSH
Related in: MedlinePlus